Clinical studies have shown that in humans, significant sex differences in susceptibility to alcohol-induced liver injury (ALI) are observed. Women are at greater risk for severe ALI than men;they develop cirrhosis more quickly and at lower alcohol dose. Some studies in rat models show similar sex differences in degree of ALI, but only rarely have direct side-by-side comparisons between male and female rats been performed. The trend towards female susceptibility to ALI suggests that the female hormone estrogen (E) may be a pathogenic cofactor in this process, since it is already known to be a factor in certain liver diseases common in women. However, any role of progesterone, the second female hormone, in ALI is completely unknown. One proposed link between female sex hormones and ALI is through a known factor in ALI, gut-derived endotoxin. Our preliminary work has shown that using a novel alcohol treatment model, male and female rats differ in that females sustain greater injury to both the liver and the gut than do males. This gut injury manifests as inflammation, loss of barrier function, and bacterial translocation. However, there are only a few studies on the effect of alcohol on gut injury, and virtually no information regarding the role of sex hormones in such injury. The work proposed tests our primary hypothesis is that female rats sustain greater ALI as a consequence of greater alcohol-induced gut injury, which leads to inflammation, loss of barrier function, increased bacterial translocation, and subsequent liver injury as a result of released endotoxin. A second hypothesis, then, is that the sex hormone status of the female is a factor in such gut and liver injury. Thus, the aims are to examine sex-specific differences in alcoholic gut and liver injury, using a novel diet shown in preliminary work to produce more significant injury to both tissues in females. In particular, we will correlate specific histopathological, biochemical, and molecular markers of injury and inflammation with changes in gene expression in both gut and liver. The second objective will determine the hormonal factors in females that result in gut and liver injury. Females will be treated with hormonal ablation and hormone treatments singly and in combination in order to determine the mechanism(s) of such injury. The research described in this proposal will lead to a greater understanding as to why women are at greater risk for alcohol-related diseases, and how their hormone status may affect the disease process. Further, we will be better able to advise women regarding use of sex hormones, for menopausal symptoms or contraception, if they consume alcohol.